3-(2-Aminoalkyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl) -6-methyluracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor

Journal of Medicinal Chemistry

Volumn 47, Issue 14, 2004, Pages 3483-3486

  Tucci, Fabio C ^a   Zhu, Yun Fei ^a   Guo, Zhiqiang ^a   Gross, Timothy D ^a   Connors Jr , Patrick J ^a   Gao, Yinghong ^a   Rowbottom, Martin W ^a   Struthers, R Scott ^a   Reinhart, Greg J ^a   Xie, Qiu ^a   Chen, Ta Kung ^a   Bozigian, Haig ^a   Bonneville, Anne L Killam ^a   Fisher, Andrew ^a   Jin, Liping ^a   Saunders, John ^a   Chen, Chen ^a  

^a NEUROCRINE BIOSCIENCES INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2,6 DIFLUOROBENZYL) 5 (2 FLUORO 3 METHOXYPHENYL) 6 METHYLURACIL DERIVATIVE; ALKYL GROUP; GONADORELIN RECEPTOR; HORMONE RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG; URACIL DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MONKEY; MOUSE; NONHUMAN; RECEPTOR BLOCKING;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; HUMANS; MACACA FASCICULARIS; MICE; RECEPTORS, LH; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

EID: 3042647364     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049791w     Document Type: Article

References (19)

1. Huirne, J. A. F.; Lambalk, C. B. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001, 358, 1793-1803.
2. Fujino, M.; Fukuda, T.; Shinagawa, S.; Kobayashi, S.; Yamazaki, I.; Nakayama, R.; Seely, J. H.; White, W. F.; Rippel, R. H. Synthetic Analogues of Luteinizing Hormone Releasing Hormone (LH-RH) Substituted in Position 6 and 10. Biochem. Biophys. Res. Commun. 1974, 60, 406-413.
3. (a) Zhu, Y.-F.; Struthers, R. S.; Connors, P. J., Jr.; Gao, Y.; Gross, T. D.; Saunders, J.; Wilcoxen, K.; Reinhart, G. J.; Ling, N.; Chen, C. Initial Structure-Activity Relationship Studies of a Novel Series of Pyrrolo[1,2-a]pyrimid-7-ones as GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 339-402.
4. (b) Zhu, Y.-F.; Wilcoxen, K.; Saunders, J.; Guo, Z.; Gao, Y.; Connors, P. J., Jr.; Gross, T. D.; Tucci, F. C.; Struthers, R. S.; Reinhart, G. J.; Xie, Q.; Chen, C. A Novel Synthesis of 2-Arylpyrrolo[1,2-a]pyrimid-7-ones and Their Structure-Activity Relationships as Potent GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 403-406.
5. (c) Wilcoxen, K.; Zhu, Y.-F.; Connors, P. J., Jr.; Saunders, J.; Gross, T. D.; Gao, Y.; Reinhart, G. J.; Struthers, R. S.; Chen, C. Synthesis and Initial Structure-Activity Relationships of a Novel Series of Imidazolo[1,2-a]pyrimid-4-ones as Potent GnRH receptor antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 2179-2184.
6. (d) Gross, T. D.; Zhu, Y.-F.; Saunders, J.; Gao, Y.; Connors, P. J., Jr.; Guo, Z.; Struthers, R. S.; Reinhart, G. J.; Chen, C. Synthesis and Structure-Activity Relationships of a Novel Series of Imidazolo[1,2-a]pyrimid-4- ones as Potent GnRH Receptor Antagonist. Bioorg. Med. Chem. Lett. 2002, 12, 2185-2187.
7. (e) Tucci, F. C.; Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Connors, P. J., Jr.; Struthers, R. S.; Reinhart, G. J.; Wang, X.; Saunders, J.; Chen, C. A Novel Synthesis of 7-Aryl-8-fluoropyrrolo[1,2-a]pyrimid-4-ones as Potent, Stable GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 3491-3495.
8. (f) Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Gao, Y.; Connors, P. J.; Struthers, R. S.; Xie, Q.; Tucci, F. C.; Reinhart, G. J.; Wu, D.; Saunders, J.; Chen, C. Design and Structure-Activity Relationships of 2-Alkyl-3-aminomethyl-6- (3-methoxyphenyl)-7-methyl-8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as Potent GnRH Receptor Antagonists. J. Med. Chem. 2003, 46, 1769-1772.
9. (g) Zhu, Y.-F.; Gross, T. D.; Guo, Z.; Connors, P. J., Jr.; Gao, Y.; Tucci, F. C.; Struthers, R. S.; Reinhart, G. J.; Saunders, J.; Chen, T. K.; Bonneville, A. L. K.; Chen, C. Identification of 1-Arylmethyl-3-(2-aminoethyl)- 5-aryluracil as Novel Gonadotropin-Releasing Hormone Receptor Antagonists. J. Med. Chem. 2003, 46, 2023-2026.
10. (h) Guo, Z.; Zhu, Y.-F.; Tucci, F. C.; Gao, Y.; Struthers, R. S.; Saunders, J.; Gross, T. D.; Xie, Q.; Reinhart, G. J.; Chen, C. Synthesis and Structure-Activity Relationships of 1-Arylmethyl-3-(2-aminopropyl)-5-aryl-6- methyluracils as Potent GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 3311-3315.
11. (i) Tucci, F. C.; Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Connors, P. J., Jr.; Struthers, R. S.; Reinhart, G. J.; Saunders, J.; Chen C. Synthesis and Structure-Activity Relationships of 1-Arylmethyl-3-(l-methyl-2-amino)ethyl-5- aryl-6-methyluracils as Antagonists of the Human GnRH Receptor. Bioorg. Med. Chem. Lett. 2003, 13, 3317-3322.
12. (j) Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. J., Jr.; Rowbottom, M. R.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart, G. J.; Chen, T. K.; Bonneville, A. L. K.; Chen, C. Synthesis and Structure-Activity Relationships of 1-Arylmethyl-5-aryl-6- methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists. J. Med. Chem. 2004, 47, 1259-1271.
13. For leading references, see the following. (a) Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.; Fujino, M. Discovery of a Thieno[2,3-d]pyrimidine-2,4-dione Bearing a p-Methoxyureidophenyl Moiety at the 6-Position: A Highly Potent and Orally Bioavailable Non-Peptide Antagonist for the Human Luteinizing Hormone-Releasing Hormone Receptor. J. Med. Chem. 2003, 46, 113-124.
14. (b) DeVita, R. J.; Walsh, T. F.; Young, J. R.; Jiang, J.; Ujjainwalla, F.; Toupence, R. B.; Parikh, M.; Huang, S. X.; Fair, J. A.; Goulet, M. T.; Wyvratt, M. J., Jr.; Lo, J.-L.; Ren, N.; Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Cui, J.; Mount, G.; Rohrer, S. P.; Schaeffer, J. M.; Rhodes, L.; Drisko, J. E.; McGowan, E.; MacIntyre, D. E.; Vincent, S.; Carlin, J. R.; Cameron, J.; Smith, R. G. A Potent, Nonpeptidyl 1H-Quinolone Antagonist for the Gonadotropin-Releasing Hormone Receptor. J. Med. Chem. 2001, 44, 917-922.
15. (c) Young, J. R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J., Jr.; Yang, Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren, R. N.; Wu, T.-J.; Shen, X.; Lyons, K. A.; Mao, A.-H.; Carlin, J. R.; Karanam, B. V.; Vincent, S. H.; Cheng, K.; Goulet, M. 2-Arylindoles as Gonadotropin Releasing Hormone (GnRH) Antagonists: Optimization of the Tryptamine Side Chain. Bioorg. Med. Chem. Lett. 2002, 12, 827-832.
16. (d) Luthin, D. R.; Hong, Y.; Tompkins, E.; Anderes, K. L.; Paderes, G.; Kraynov, E. A.; Castro, M. A.; Nared-Hood, K. D.; Castillo, R.; Gregory, M.; Vazir, H.; May, J. M.; Anderson, M. B. Characterization of Mono- and Diaminopyrimidine Derivatives as Novel, Nonpeptide Gonadotropin Releasing Hormone (GnRH) Receptor Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 3635-3639.
17. Perrin, M. H.; Haas, Y.; Rivier, J. E.; Vale, W. W. Mol Pharmacol. 1983, 23, 44. For experimental procedures detailing the binding assay, please refer to the Supporting Information.
18. On each assay plate a standard antagonist of affinity comparable to those being tested was included as a control for plate-to-plate variability. All compounds were assayed in three to eight independent experiments.
19. For experimental details of the hGnRH functional assay, please refer to the Supporting Information.